As detection methods become more sophisticated, there is an increasing realization that viruses can reside within apparently normal hosts for extended periods. During such long-term infections, virus reactivation may occur spontaneously or after changes in the immunological status of the host. The onset of virus replication may initiate pathogenic events by provoking immune responses against the virus and virus infected cells and/or from virus disruption of cellular functions. The significance of long-term infections for human disease processes is only now becoming fully apparent and there have been several suggestions that viruses may be involved with chronic degenerative diseases. At present, there is only limited understanding of the molecular events associated with the establishment and maintenance of long-term virus infections both with respect to alterations in virus gene expression and virus-induced changes within the infected individual. I intend to study a well-characterized and reproducible model system, based on persistent infections of laboratory mice and tissue culture cells with lymphocytic choriomeningitis virus, to identify regulatory events that mediate the transition from acute to persistent infection and subsequent maintenance of the persistent infection. A detailed explanation for the molecular basis of virus persistence in one system will allow conceptual developments for the whole field of virus persistence and may suggest strategies for intervention and eventual clearance of a persistent infection.